Antimicrobial coatings for medical devices

ABSTRACT

Antimicrobial formulations and coatings for medical devices and processes therefor are disclosed. The formulations include at least one water permeable polymer with at least one antimicrobial agent in a liquid medium and are prepared by wet milling the components and can form antimicrobial coatings having uniformly dispersed particles having an average size of no greater than 50 microns.

This application is a continuation of U.S. patent application Ser. No.15/700,446, filed Sep. 11, 2017, which is a divisional of U.S. patentapplication Ser. No. 14/567,183, filed Dec. 11, 2014. The entire contentof each of these applications is incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to antimicrobial formulations andcoatings for medical devices and in particular implantable medicaldevices.

BACKGROUND

Implantable medical devices used for patient treatment can be a sourceof microbial infection in such patients. For example, insertion orimplantation of a medical device into a patient can introduce microbesthat can cause infection. To reduce or minimize the impact of theintroduction of microbes to a patient, many medical devices, such ascatheters, have been coated with antimicrobial agents.

However, many antimicrobial agents that are useful in coating medicaldevices tend to be insoluble in formulations used to coat the device andtend to form agglomerated particles on the surface of the medicaldevice. These agglomerated particles increase the surface roughness ofthe medical device, thus increasing the chance for thrombus formation onthe surface of the medical device, and are more readily detached fromthe surface thereby reducing the long term efficacy of the antimicrobialcoating. Further, agglomerated particles in the antimicrobialformulation that is used to coat the medical device may lead to activematerial precipitating out of the formulation and therefore not beingcoated onto the medical device, or otherwise interfering with thecoating process. Accordingly, a need exists for improved antimicrobialcoatings on implantable medical devices.

SUMMARY OF THE DISCLOSURE

An advantage of the present invention is an implantable medical devicehaving an antimicrobial coating including a water permeable polymer anduniformly dispersed particles therein of at least one antimicrobialagent. The present disclosure provides an antimicrobial formulation withlittle to no agglomerated particles, which can be stored over a longperiod of time before coating a medical device. Also, once coated onto amedical device, the coating provides a consistent elution ofantimicrobial agents over a longer period of time.

These and other advantages are satisfied, at least in part, by a processof forming an antimicrobial formulation for coating a medical device.The process comprises milling at least one water permeable polymer withat least one antimicrobial agent in a liquid medium to form theantimicrobial formulation. Advantageously, the milling causes the waterpermeable polymer to encapsulate at least a portion of the antimicrobialagent.

An aspect of the present disclosure includes an antimicrobialformulation for coating a medical device. The formulation includes atleast one water permeable polymer and particles of at least oneantimicrobial agent in a liquid medium, wherein the formulation includesuniformly dispersed particles in the liquid medium with no agglomeratedparticles greater than 50 microns in size. The formulation can beprepared by milling the formulation.

Embodiments include any one or more of the following features,individually or combined. For example, the at least one polymer caninclude at least one of a polyurethane, thermoplastic polyurethaneelastomer, polyester, polylactic acid, polyglycolic acid,polytetramethylene glycol, polyacrylamide, polyacrylic acid,polyacrylate, poly(2-hydroxyethyl methacrylate), polyethylene-imine,poly-sulfonate and copolymers thereof. In some embodiments, the at leastone polymer has a weight average molecular weight of from about 70,000to about 120,000 Daltons. In various embodiments, the at least oneantimicrobial agent includes a combination of a silver-basedantimicrobial agent and a polybiguanide or salt thereof. In stillfurther embodiments, the silver-based antimicrobial agent includes oneor more of silver particles, a silver nitrate, silver halide, silveracid salt, silver permanganate, silver sulfate, silver nitrite, silverchromate, silver carbonate, silver phosphate, silver (I) oxide, silversulfide, silver azide, silver sulfite, a silver thiocyanate or a silversulfonamide. In various embodiments, the polybiguanide or salt thereofincludes one or more of chlorhexidine dihydrochloride, chlorhexidinediacetate or chlorhexidine digluconate. In some embodiments, the atleast one antimicrobial agent includes a combination of silversulfadiazine and chlorhexidine diacetate. In various embodiments, theliquid medium includes one or more of an alcohol; an ether; a ketone; anorganic acid; an organic ester; an amide; a hydrocarbon; or ahalogenated solvent or liquid. In still further embodiments, the liquidmedium includes an ether and a primary C₁₋₆ alcohol. In variousembodiments, the at least one antimicrobial agent is insoluble in theformulation and the formulation is milled until the insolubleantimicrobial agent has a mean particle size of no greater than about 50microns. In some embodiments, the formulation includes from about 70 wt% to 90 wt % of a polyurethane polymer, from 2 wt % to about 10 wt %silver sulfadiazine, and at least 9 wt % of chlorhexidine diacetate.

In an aspect of the present disclosure, the process can compriseinitially preparing a polymer solution having a viscosity in a range offrom about 100 centipoise (cP) to about 1000 cP, for example, bydissolving the polymer in the liquid medium and then adding theantimicrobial agent to the solution followed by milling the formulation.The process can further comprise adding a second antimicrobial agent tothe formulation after milling, and further milling the formulation withthe second antimicrobial agent and further comprise adding a primaryC₁₋₆ alcohol to the formulation after milling the formulation with thesecond antimicrobial agent.

In another aspect of the present disclosure, the process of forming anantimicrobial formulation for coating a medical device can comprisemilling at least one water permeable thermoplastic polyurethaneelastomer with a silver-based antimicrobial agent and a polybiguanide orsalt thereof antimicrobial agent in a liquid medium to form theantimicrobial formulation. The process can further comprise: preparing asolution having a viscosity of from about 100 centipoise (cP) to about1000 cP by dissolving the thermoplastic polyurethane elastomer in theliquid medium; adding the silver-based antimicrobial agent to thesolution followed by milling to form a formulation; adding thepolybiguanide or salt thereof antimicrobial agent to the formulationfollowed by milling to form the antimicrobial formulation; and adding aprimary C₁₋₆ alcohol to the antimicrobial formulation. Advantageously,the milling can result in a formulation with significantly uniformlydispersed particles and with no, or very few, agglomerated particlesgreater than 50 microns.

Another aspect of the present disclosure includes a process of formingan antimicrobial coating on a medical device. The process comprisesapplying an antimicrobial formulation having at least one waterpermeable polymer and at least one antimicrobial agent on a medicaldevice to form an antimicrobial coating on the medical device, whereinthe antimicrobial formulation is formed by milling the at least onepolymer with the at least one antimicrobial agent in a liquid medium.

Embodiments include any one or more of the features described for theprocess of forming the antimicrobial formulation and/or formulationand/or any one or more of the following features, individually orcombined. In addition, the medical device can be selected from the groupconsisting of a dialysis catheter, a urological catheter, an enteralfeeding tube, a surgical staple, a trocar, an implant, suture, arespiratory tube, a surgical plate, a surgical screw, a wire, and ahernia mesh. In some embodiments, the coating has a thickness in a rangeof between about 20 microns to about 80 microns. In various embodiments,applying the formulation on the medical device comprises dip-coating themedical device in the formulation and then drying the antimicrobialformulation by driving off the liquid medium to form the antimicrobialcoating on the medical device. In embodiments, the at least one polymerincludes a polyurethane polymer and the at least one antimicrobial agentincludes a combination of a silver-based antimicrobial agent and apolybiguanide or salt thereof. In various embodiments, the at least oneantimicrobial agent includes a combination of silver sulfadiazine andchlorhexidine diacetate.

Another aspect of the present disclosure includes a device having anantimicrobial coating, wherein the coating comprises a polymer anduniformly dispersed particles of at least one antimicrobial agent andwherein the particles and any agglomerations of the antimicrobial agenthave an average size of no greater than 50 microns.

Embodiments include any one or more of the features described for theantimicrobial formulation and/or the process of forming theantimicrobial formulation and/or the process of forming the coating onthe medical device and/or any one or more of the following features,individually or combined. In addition, the at least one antimicrobialagent can be a silver-based antimicrobial agent. In some embodiments,the at least one antimicrobial agent is a silver sulfadiazine. Invarious embodiments, the at least one antimicrobial agent is a silversulfadiazine and wherein the coating has a release profile wherein atleast 0.50 μg/cm of silver is continuously released after 72 hours. Instill further embodiments, the coating further comprises chlorhexidinediacetate and/or the coating further comprises chlorhexidine diacetateand at least 10 μg/cm of chlorhexidine diacetate is continuouslyreleased after 72 hours. In various embodiments, the antimicrobialcoating is formed on the device by applying an antimicrobial formulationhaving at least one water permeable polymer and at least oneantimicrobial agent on the medical device. In embodiments, theantimicrobial formulation is formed by milling the at least one polymerwith the at least one antimicrobial agent in a liquid medium. In someembodiments, the antimicrobial coating includes from about 70 wt % to 90wt % of a polyurethane polymer, from 2 wt % to about 10 wt % silversulfadiazine, and at least 9 wt % of chlorhexidine diacetate.

Additional advantages of the present invention will become readilyapparent to those skilled in this art from the following detaileddescription, wherein only the preferred embodiment of the invention isshown and described, simply by way of illustration of the best modecontemplated of carrying out the invention. As will be realized, theinvention is capable of other and different embodiments, and its severaldetails are capable of modifications in various obvious respects, allwithout departing from the invention. Accordingly, the drawings anddescription are to be regarded as illustrative in nature, and not asrestrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

Reference is made to the attached drawings, wherein elements having thesame reference numeral designations represent similar elementsthroughout and wherein:

FIG. 1 is a chart showing the release profile of a catheter coated withchlorhexidine acetate (CHA) prepared in accordance with the presentdisclosure compared to a commercial catheter having an antimicrobialcoating including CHA.

FIG. 2 is a chart showing the release profile of silver from anantimicrobial coating in accordance with the present disclosure comparedto a commercially available catheter having an antimicrobial coatingincluding silver.

FIG. 3 is a chart showing the results of bacterial challenge testing(BAC) for catheter samples having an antimicrobial coating in accordancewith the present disclosure compared to two catheter samples of acommercially available catheter having an antimicrobial coating.

FIGS. 4A and 4B are SEM images of antimicrobial coatings on medicaldevices. FIG. 4A shows an SEM image of an antimicrobial coating that wasprepared from an antimicrobial formulation which was prepared by millingthe components of the formulation and FIG. 4B shows an SEM image of anantimicrobial coating from the same formulation which was prepared bymixing, not milling the components.

FIGS. 5A and 5B are SEM images of antimicrobial coatings on medicaldevices. FIG. 5A shows an SEM image of an antimicrobial coating preparedin accordance with the present disclosure. FIG. 5B shows an SEM image ofa commercially available catheter having an antimicrobial coating.

FIGS. 6A and 6B are SEM images of antimicrobial coatings on medicaldevices. FIG. 6A shows an SEM image of an antimicrobial coating preparedin accordance with the present disclosure. FIG. 6B shows an SEM image ofa commercially available catheter having an antimicrobial coating.

FIG. 7 is a particle size distribution chart of an antimicrobialformulation prepared in accordance with the present disclosure.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure is directed to antimicrobial formulations thatcan be applied to medical devices to form antimicrobial coatingsthereon. The present disclosure is particularly applicable toimplantable medical devices, such as catheters, enteral feeding tubes,surgical staples, respiratory tubes, surgical plates, surgical screws,wires, and hernia mesh, and forming antimicrobial coatings thereon.

Since many polymers and/or antimicrobial agents that are useful forforming antimicrobial coatings on medical devices are not readilysoluble, such ingredients tend to form agglomerated particles in theformulations used to coat a medical device as well as on the surface ofthe medical device. Agglomerated particles can form in sizes as large asseveral hundred microns even when the initial size of the particles usedin preparing a formulation is as small as several microns. Theseagglomerated particles are due to the agglomeration of many smallersized particles that agglomerate during the coating process.

These agglomerated particles adversely increase the surface roughness ofthe medical device. In addition, the size and shape of the agglomeratedparticles can adversely affect the dissolution or release of theantimicrobial agent from the coating.

Antimicrobial formulations of the present disclosure are prepared bymilling the various ingredients, thereby minimizing the size of theinsoluble particles and their tendency to agglomerate. Surprisingly, ithas been found that by milling the various components as set forthbelow, not only is the coating prepared from the formulation more smoothonce coated on a medical device, but also the elution rate of theantimicrobial agents becomes more consistent over time, and the releaserate appears to be better controlled over a longer period of time.Further, re-agglomeration of the insoluble antimicrobial components iseliminated, or nearly eliminated.

In practicing embodiments of the present disclosure, an antimicrobialformulation for coating a medical device can be formed by milling atleast one polymer with at least one antimicrobial agent in a liquidmedium to form the antimicrobial formulation. Preferably, the milling isdone by a high-shear miller that reduces particle size and preventsagglomeration of particles in the formulation. Formulations containingone or more insoluble ingredients are particularly useful in practicingthe present disclosure. Such formulations contain a liquid medium, atleast one polymer, and at least one antimicrobial agent that is notsoluble in the formulation. The formulation can also include otheringredients that are useful in forming antimicrobial coatings onimplantable medical devices.

Polymers useful for practicing the present disclosure include those thatare water permeable and are used for coating medical devices such as,for example, a polyurethane, such as a thermoplastic polyurethaneelastomer, a polyester, polylactic acid, polyglycolic acid,polytetramethylene glycol, polyacrylamide, polyacrylic acid,polyacrylate, poly(2-hydroxyethyl methacrylate), polyethylene-imine,poly-sulfonate and copolymers thereof such as poly(lacticacid-co-glycolic acid) (PLA/PGA), polyacrylic-co-hydroxylated-acrylate,poly(acrylic acid-co-2-hydroxy ethyl methacrylate). In one aspect of thepresent disclosure, the polymer is a thermoplastic polyurethaneelastomer, such as Pellethane which is available from Lubrizol AdvancedMaterials, USA.

The molecular weight of the polymer is preferably high enough to form auseful coating on the medical device but not so high as to prevent theformulation from flowing over the medical device and forming thecoating. Such polymers have a weight average molecular weight, forexample, of from about 20,000 to about 500,000 Daltons, e.g. betweenabout 50,000 to about 200,000, between about 70,000 to about 120,000Daltons. The weight average molecular weights can be determined by usingGPC analysis having a refractive index detector coupled with a lightscattering detector for absolute molecular weight measurement of weightaverage molecular weight (M_(w)).

Antimicrobial agents that are useful for the present disclosure include,for example, silver-based antimicrobial agents; polybiguanides and saltsthereof; chlorhexidine and salts thereof such as the dihydrochloride,diacetate and digluconate salt of chlorhexidine; hexachlorophene;cyclohexidine; chloroaromatic compounds such as triclosan;para-chloro-meta-xylenol.

Silver-based antimicrobial agents include, for example, silverparticles; a silver nitrate; silver halides, e.g., silver fluoride,chloride, bromate, iodate; silver acid salts, e.g., silver acetate,silver salicylate, silver citrate, silver stearate, silver benzoate,silver oxalate; silver permanganate; silver sulfate; a silver nitrite;silver dichromate; silver chromate; silver carbonate; silver phosphate;silver (I) oxide; silver sulfide; silver azide; silver sulfite; silverthiocyanate; and silver sulfonamide, such as a silver sulfadiazine.Antimicrobial agents that are not readily soluble in a formulation areparticularly advantageous in the present disclosure.

In one embodiment of the present disclosure, the antimicrobial agentsinclude a combination of a silver-based salt and a polybiguanide salt,i.e., a combination of silver sulfadiazine and chlorhexidine diacetate.

The liquid medium of the present disclosure includes one or more liquidsthat are useful for coating a medical device and dissolving orsuspending the polymer and/or antimicrobial agent. Such liquids include,for example, one or more of the following: an alcohol and lower alcohol,e.g., a C₁₋₁₂ alcohol, such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, furfuryl alcohol; a polyhydridicalcohol, such as ethylene glycol, a butanediol, a propanediol; an ether,such as a linear, branched or cyclic lower ether, dimethyl ether, ethylether, methyl ethyl ether, tetrahydrofuran; a ketone such as a linear,branched or cyclic lower ketone, such as acetone, methyl ethyl ketone,cyclohexanone; an organic acid, such as formic acid, acetic acid,butyric acid, benzoic acid; an organic ester, such as a formate, ethylor methyl acetate, propionate; an amide such as a linear, branched orcyclic lower amide, such as dimethylacetamide (DMAC), pyrrolidone,1-Methyl-2-pyrrolidinone (NMP), a hydrocarbon, such as a linear,branched or cyclic alkane, such as a pentane, hexane, heptane, octane,cyclohexane, a linear, branched or cyclic alkene, an aromatic solvent orliquid; and a halogenated solvent or liquid such as a chlorinatedsolvent or liquid.

In one aspect of the present disclosure, the liquid medium includes aprimary alcohol, e.g., a primary C₁₋₆ alcohol such as methanol, ethanol,n-propanol, n-butanol, n-pentanol, n-hexanol in the formulation. It wasfound that use of a primary C₁₋₆ alcohol, such as n-propanol,facilitates coating of the medical device. It was found that n-propanolhas a beneficial balance between the length of the aliphatic chain andthe hydroxyl group. Also, when used with THF, n-propanol has a desirableboiling point of 99° C., which allows it to stay at the coating surfacelonger than THF which in turn improves flow and leveling of the coatingon the medical device surface.

Milling the one or more polymers and antimicrobial agents in liquidmedia offers the advantage of forming uniform antimicrobial formulationsthat can be used to coat medical devices. It is believed that milling,rather than mixing such as with a high shear mixer, a liquid mediumincluding the at least one water permeable polymer with the at least oneantimicrobial agent enables the antimicrobial agent to be uniformlydispersed in the liquid medium and/or to be encapsulated within thepolymer such that the antimicrobial agent does not re-agglomerate priorto and during coating of a medical device. The encapsulated agent in theformulation is believed to provide a more consistent elution rate andprevent the re-agglomeration of particles over time. Milling theformulation can be carried out using a high-shear miller such as a rollmill. Milling media useful for the present disclosure include Yttriastabilized zirconia grinding media, ⅜ inch cylinder shape, from InframatAdvanced Materials.

In one aspect of the present disclosure, at least one antimicrobialagent is insoluble in the formulation and the formulation is milleduntil the insoluble antimicrobial agent has a mean particle size of nogreater than about 50 microns, such as no greater than 40 microns, 30microns, 20 microns, 10 microns, 5 microns and numbers therebetween. Inone embodiment, the mean particle size is approximately 5 microns. Meanparticle size determinations can be made by a laser diffraction particlesize analyzer, such as the Microtrac S3500 with a circulating loop tosuspend the sample during analysis.

In an embodiment of the present disclosure, the milling process caninclude initially preparing a polymer solution. Such polymer solutionspreferably have a viscosity and wetting properties that allows theformulation to smoothly flow over the surface of the device tofacilitate forming a uniform coating on the medical device. The amountof the polymer in the formulation to provide an appropriate viscositywill depend on the polymer, liquid medium and molecular weight of thepolymer.

Viscosities suitable for the formulation range from about 100 centipoise(cP) to about 10,000 cP, e.g. from about 100 cP to about 1,000 cP,preferably from about 500 cP to about 1000 cP. Typically from about 5 wt% to 30 wt % of the polymer can be combined with the liquid medium toform the solution with the appropriate viscosity. In an embodiment ofthe present disclosure, preparing an antimicrobial formulation includesinitially preparing a polymer solution having a viscosity of from about100 centipoise (cP) to about 1,000 cP by dissolving the polymer in theliquid medium and then adding the antimicrobial agent to the solutionfollowed by milling the formulation.

Additional antimicrobial agents can be added to such a formulation. Suchadditional antimicrobial agents can be added neat or in a solution witha liquid medium such as in a primary C₁₋₆ alcohol. After addingadditional antimicrobial agents, the formulation can be milled to form amore or less homogeneous mixture with particles having a mean particlesize of no greater than about 50 microns, such as no greater than 40microns, 30 microns, 20 microns, 10 microns, 5 microns and numbers therebetween.

Medical devices can be prepared having antimicrobial coatings from theformulations of the present disclosure. In practicing certainembodiments of the present disclosure, an antimicrobial coating on amedical device can be prepared by applying an antimicrobial formulationhaving at least one polymer and at least one antimicrobial agent on amedical device. The application of the formulation to the device can beby a dip-coating process or by a spraying process, for example. Asdescribed above, a formulation including at least one insolubleingredient is particularly advantageous in practicing the presentdisclosure. The formulation is formed by milling the at least onepolymer with the at least one antimicrobial agent in a liquid medium.

Medical devices that can be coated by the processes described in thepresent disclosure include, for example, any medical device intended tobe implanted in a patient such as dialysis catheters, urologicalcatheters, enteral feeding tubes, staples, trocars, implants, titaniumimplants, respiratory tubes, surgical plates, surgical screws, wires,hernia mesh, and sutures.

This formulation can be applied to the medical device in any way thatallows the formulation to flow over and coat the device. For example,the formulation can be applied by a dip-coating process wherein themedical device is dipped into a container holding the formulation andthen removed from the container. The formulation is then allowed to dryon the device. Drying can include heating the coated medical device orallowing the medical device to dry at room temperature. In an embodimentof the present invention, the formulation includes a polyurethanepolymer and an antimicrobial agent that includes a combination of asilver based antimicrobial agent and a polybiguanide or salt thereof,i.e., a combination of silver sulfadiazine and chlorhexidine diacetate.

The thickness of the antimicrobial coating on the medical device willdepend on the application of the medical device. For example, whencoating a dialysis catheter the coating can have a thickness of betweenabout 20 microns to about 80 microns (e.g., between about 65 to about 45microns such as about 55 microns). Different implantable medical devicescan have the same thickness of coatings depending on the intended use.

In practicing embodiments of the present disclosure, a medical devicecan be prepared having an antimicrobial coating which includes a polymerand particles of at least one antimicrobial agent wherein the particlesof the antimicrobial agent have an average size of no greater than theaverage particle size of the antimicrobial agent in the initialformulation. That is, the mean particle size of the antimicrobial agenton or in the coating is no greater than about 50 microns, 40 microns, 30microns, 20 microns, 10 microns, 5 microns and numbers therebetween.

Advantageously, the particles formed in the formulation after millingresist agglomeration both in the bulk formulation and when prepared as acoating on the medical device. The coating can contain particles havinga mean particle size and mean agglomeration size of no greater thanabout 50 microns, 40 microns, 30 microns, 20 microns, 10 microns, 5microns, and numbers therebetween.

The solubility of the antimicrobial agents and the water permeability ofthe polymer will affect the release rate of the antimicrobial agent fromthe coating. For example more soluble antimicrobial agents such aschlorhexidine gluconate will have a high release rate whereas therelatively water insoluble hydrochloride salt releases slowly. In oneembodiment of the present disclosure, the coating on the medical devicehas a nominal formulation that includes from about 70 wt % to 90 wt % ofa polyurethane polymer, from 2 wt % to about 10 wt % silversulfadiazine, e.g. from about 3.5 wt % to about 7 wt % and a minimumamount of CHA of about 9 wt %, 10 wt %, or about 11 wt %. Such a coatingcan be formed to have a release profile wherein at least 0.50 μg/cm ofsilver is continuously released after 75 hours, e.g., after about 100hours, 150 hours and higher, and wherein at least 10 μg/cm ofchlorhexidine diacetate is continuously released after 75 hours e.g.,after about 100 hours, 150 hours and higher.

EXAMPLES

The following examples are intended to further illustrate certainpreferred embodiments of the invention and are not limiting in nature.Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific substances and procedures described herein.

A series of antimicrobial formulations were prepared by initiallypreparing an approximate 12 wt % polymer solution. This was accomplishedby combining a thermoplastic polyurethane elastomer polymer (Pellethane2363-80A thermoplastic polyurethane polymer available from Lubrizol)with Tetrahydrofuran (THF) in a polymer reactor. Four differentthermoplastic polyurethane elastomer polymers were used which had weightaverage molecular weights of about 82,400, 89,700, 90,400, and 105,900Daltons, which were determined by GPC equipped with a refractive indexdetector coupled with a light scattering detector for absolute molecularweight measurement (M_(w)). These polymer solutions had Brookfieldviscosity values of 1167, 1686, 1533, and 3965 cP, respectively asdetermined from a Brookfield viscometer in THF with approximately 12.5wt % solids. The polymer reactor was configured with a reflux condenser,stirring mechanism and Nitrogen gas inlet to provide a constant Nitrogenblanket in the reactor. THF was added to the reactor and thepolyurethane polymer was added to a level of 12.3 weight percent solids,and the mixture was heated with mixing at 45-55° C. for 16 hours, thencooled to ambient temperature to form the solution containing thepolymer. The percent solids of the polyurethane polymer solution wasmeasured gravimetrically, by placing a sample on an aluminum weighingdish in a lab oven at 110° C. for 60 minutes.

A mixture containing the polymer solution utilizing the polyurethanehaving a molecular weight of 89,700 Daltons and a silver-basedantimicrobial agent was then prepared by combining 181.22 grams of thepolyurethane polymer/THF solution with 91.78 grams of THF and with 2.81grams of silver sulfadiazine (AgSD) in a one (1) quart sealed glass jarmilling vessel together with milling media, i.e., zirconia grindingmedia. This mixture was then milled for 24 hours in the sealed glass jarmilling vessel on a roll mill using 555 grams (114 media pieces) ofYttria stabilized Zirconia grinding media ⅜ inch cylinder shape(available from Inframat Advanced Materials). The milling rate was setto about 50 rpm for this and subsequent milling.

A mixture of chlorhexidine acetate (CHA) (available from Medichem, S.A.,Barcelona Spain) was separately prepared by combining 4.64 grams of CHAwith 9.30 grams of methanol with mixing until complete dissolution wasachieved. Then 12.4 grams of THF was slowly added to the CHA/methanolsolution with mixing.

The CHA/methanol/THF solution was then added to the milling vesselcontaining the polyurethane/THF/AgSD mixture, with mixing, in incrementsof equal volume at approximately every 1 hour interval for a total 6hour time period. This mixture was then milled for 24 hours.

Additional processing aids and solvents can be added to the milledmixture. For this example, approximately 98.6 grams of n-propanol wasadded in increments of equal volume over 2 hours while milling, and themixture was milled for an additional 3 hours to provide an antimicrobialformulation. Milling was conducted throughout the n-propanol addition.N-propanol was added in 2 increments of equal volume, then milled for anadditional 3 hours. For this example, n-propanol was the let-backsolvent used to dilute the formulation to reduce the overall amount ofthe THF, and to provide improved flow/leveling of the coating on drying.This formulation had the following weight percentages:

TABLE 1 Example Antimicrobial Formulation Ingredient Approximate Weight% Polyurethane polymer 8.41 AgSD 0.70 CHA 1.16 THF 62.81 Methanol 2.32n-propanol 24.60 Total 100

The percent solids of the formulation was measured gravimetrically, byplacing a sample on an aluminum weighing dish in a lab oven at 110° C.for 60 minutes. The viscosity of the formulation was measured using aBrookfield viscometer.

The particle sizes for AgSD after milling is shown in FIG. 7. Theparticle sizes for AgSD after milling had a distribution wherein the 50percentile value was approximately 5.4 microns and 90% of the particleswere 30 microns or less. The mean particle size was 5.4 microns. Theforegoing particle sizes were determined by a laser diffraction particlesize analyzer, the Microtrac S3500 with a circulating loop to suspendthe sample during analysis. Specifically, the formulation was stirred ona lab stir plate with a stir bar at 600 rpm for 2 hours. The formulationwas diluted with tetrahydrofuran (THF) solvent to adjust the viscosityinto the appropriate range for the instrument, and automatic mixing ofthe sample was maintained throughout the particle size measurements togenerate the particle size distribution chart shown in FIG. 7. While theparticle size distribution shows few particles over 100 microns, it isbelieved, based on SEM images of the coating, that few particles areactually over 50 microns, and that the population at the high end of thedistribution chart may actually be the laser detecting multipleparticles in close proximity to each other while the diluted sample wasmixing during analysis.

The antimicrobial formulation was used to prepare an antimicrobialcoating on the exterior of the dialysis catheter surface. This wasaccomplished by placing the formulation in a suitable vessel inside anautomated dip-coating apparatus (appropriately vented) and submergingthe catheter shaft into the formulation. The catheter was then dried ina vented oven at 60° C. for 5 days to remove the solvents. The coatingprepared in this example was composed approximately of 81.88 wt %polyurethane polymer, 11.30 wt % CHA and 6.82% AgSD. The thickness ofthe coating was measured by obtaining a cross-section of the catheter atvarious intervals and obtaining the coating thickness by measurement ona Scanning Electron Microscope. The thickness was determined to be about55 microns.

Catheters prepared according to this example were tested for the releaserates of the antimicrobial agents in phosphate buffered saline (PBS)solution. The release rates were determined by taking samples of PBSsolution from a container holding cut samples of the coatings of eachcatheter. For each catheter, several samples of the coating wereprepared by cutting the coated catheter to a particular size. The cutsamples were then combined with PB S solution in a sample containermounted on a shaker which was set to 37° C. and 120 rpm. The cut coatingsamples were then removed from the container and placed in new samplecontainers with PBS solutions first at the 4 hour mark, then at every 24hours thereafter. The PBS solutions were then analyzed for antimicrobialcontent. Chlorhexidine was analyzed by HPLC and silver concentration wasanalyzed by ICP-MS.

Release rates for the antimicrobial agents were measured as describedabove and the results plotted in the charts shown in FIGS. 1 and 2.FIGS. 1 and 2 also plot the release rates of a commercially availablecatheter, the ARROWgard Blue™ hemodialysis catheter available fromTeleflex Medical (Research Triangle Park, N.C.), having an antimicrobialcoating including AgSD and CHA. The ARROWgard Blue™ catheter has beencommercially available since approximately 1990, and it is believed,based on Food and Drug Administration filings, that the only change tothe antimicrobial coating since its commercial release has been anincrease in the antimicrobial material amounts. The ARROWgard Blue™catheter samples were prepared and analyzed in PBS as described above.As shown in FIGS. 1 and 2, catheters coated with a formulation accordingto the present disclosure had at least 10 μg/cm of chlorhexidinediacetate released after 72 hours and a release profile wherein at least0.50 μg/cm of silver was released after 72 hours. For this particularexample, the 10 μg/cm of chlorhexidine diacetate released after 150hours and had a release profile wherein at least 0.50 μg/cm of silverwas released after 150 hours.

Catheters prepared according to this example were also compared to thecommercially available ARROWgard Blue™ catheter for antimicrobialeffectiveness. FIG. 3 shows Bacterial Challenge (BAC) Testing of thecatheters. The data show that catheters coated with formulations of thepresent disclosure had superior antimicrobial activity across all 3microorganisms as compared to the commercially available catheter.

To demonstrate the benefits of milling the components of anantimicrobial formulation, a comparative example was undertaken. Twoseparate antimicrobial formulations were prepared with the same polymer,antimicrobial agents and liquid media. One formulation was prepared bymilling the components while the other formulation was prepared bymixing the components. Coatings were then prepared from the twoformulation and the coatings were analyzed by SEM. The SEM images areshown in FIGS. 4A and 4B. FIG. 4A shows an SEM image of an antimicrobialcoating that was prepared from the formulation with milling and FIG. 4Bshows an SEM image of the formulation prepared by mixing, not millingthe components.

As shown in FIGS. 4A and 4B, the antimicrobial formulation that wasprepared by a process that included milling of the components resultedin a coating with uniformly dispersed particles, with uniformly sizedparticles and with no agglomerated particles greater than 20 microns. Ascan be seen from FIG. 4B, the antimicrobial formulation prepared withoutmilling resulted in a coating with a non-uniform distribution ofparticles and agglomerated particles of greater than 50 microns. In FIG.4B, a 53 micron and 322 micron agglomerated particle were visible in theimage.

Similarly, SEM imaging was conducted of an antimicrobial coating thatwas prepared from the formulation of the present disclosure (shown inFIG. 5A), as well as the commercially available ARROWgard Blue™ catheter(shown in FIG. 5B). As shown in FIG. 5A, the antimicrobial formulationthat was prepared by a process that included milling of the componentsas described above resulted in a coating with uniformly dispersedparticles, with uniformly sized particles and with no agglomeratedparticles greater than 20 microns. As can be seen from FIG. 5B, theantimicrobial coating on the commercially available ARROWgard Blue™catheter has a coating with a non-uniform distribution of particles andagglomerated particles of greater than 20 microns.

SEM imaging was conducted of an antimicrobial coating that was preparedfrom the formulation of the present disclosure (shown in FIG. 6A), aswell as the commercially available ARROWgard Blue™ catheter (shown inFIG. 6B) to show the surface texture. As shown in FIG. 6A, theantimicrobial formulation that was prepared by a process that includedmilling of the components as described above resulted in a coating witha smooth outer surface. As can be seen from FIG. 6B, the antimicrobialcoating on the commercially available ARROWgard Blue™ catheter has acoating with a surface texture that is less smooth in appearance thanthat of the coating of the present disclosure.

Only the preferred embodiment of the present invention and examples ofits versatility are shown and described in the present disclosure. It isto be understood that the present invention is capable of use in variousother combinations and environments and is capable of changes ormodifications within the scope of the inventive concept as expressedherein. Thus, for example, those skilled in the art will recognize, orbe able to ascertain, using no more than routine experimentation,numerous equivalents to the specific substances, procedures andarrangements described herein. Such equivalents are considered to bewithin the scope of this invention, and are covered by the followingclaims.

What is claimed is:
 1. A medical device comprising an antimicrobialcoating, wherein the coating comprises at least one water permeablepolymer and uniformly dispersed particles therein of at least oneantimicrobial agent, and wherein the particles and any agglomerations ofthe antimicrobial agent have an average size of no greater than 50microns.
 2. The medical device of claim 1, wherein the average size isno greater than 20 microns.
 3. The medical device of claim 2, whereinthe average size is no greater than 5 microns.
 4. The medical device ofclaim 1, wherein the at least one water permeable polymer encapsulatesthe at least one antimicrobial agent.
 5. The medical device of claim 1,wherein the at least one water permeable polymer includes at least oneof a polyurethane or a thermoplastic polyurethane elastomer.
 6. Themedical device of claim 1, wherein the at least one polymer includes atleast one of a polyurethane, thermoplastic polyurethane elastomer,polyester, polylactic acid, polyglycolic acid, polytetramethyleneglycol, polyacrylamide, polyacrylic acid, polyacrylate,poly(2-hydroxyethyl methacrylate), polyethylene-imine, poly-sulfonateand copolymers thereof.
 7. The medical device of claim 1, wherein the atleast one polymer has a weight average molecular weight of from about70,000 to about 120,000 Daltons.
 8. The medical device of claim 1,wherein the at least one antimicrobial agent comprises silversulfadiazine, and wherein the coating has a release profile wherein atleast 0.50 micrograms per centimeter (μg/cm) of silver is continuouslyreleased after 72 hours.
 9. The medical device of claim 1, wherein thecoating further comprises chlorhexidine diacetate, and at least 10 μg/cmof chlorhexidine diacetate is continuously released after 72 hours. 10.The medical device of claim 1, wherein the at least one antimicrobialagent comprises a silver-based salt and a polybiguanide salt.
 11. Themedical device of claim 10, wherein the silver-based salt is silversulfadiazine, and the polybiguanide salt is chlorhexidine diacetate. 12.The medical device of claim 11, wherein the coating comprises from about2 weight percent (wt. %) to about 10 wt. % of silver sulfadiazine,wherein the coating comprises at least 9 wt. % of chlorhexidinediacetate, and wherein the coating comprises from about 70 wt. % toabout 90 wt. % of the water permeable polymer.
 13. The medical device ofclaim 12, wherein the coating comprises from about 3.5 wt. % to about 7wt. % silver sulfadiazine.
 14. The medical device of claim 13, whereinthe coating has a release profile wherein at least 0.50 μg/cm of silveris continuously released after 150 hours.
 15. The medical device ofclaim 12, wherein the coating comprises at least 11 wt. % ofchlorhexidine diacetate.
 16. The medical device of claim 15, wherein thecoating has a release profile wherein at least 10 μg/cm of chlorhexidinediacetate is continuously released after about 150 hours.
 17. Themedical device of claim 1, wherein the coating has a thickness ofbetween about 20 microns to about 80 microns.
 18. An antimicrobialformulation for coating a medical device prepared according to a processcomprising: milling at least one water permeable polymer which isdissolved in a liquid medium with at least one antimicrobial agent whichis insoluble in the liquid medium to form the antimicrobial formulationin which the at least one water permeable polymer encapsulates the atleast one antimicrobial agent; and adding a primary C₁₋₆ alcohol to theantimicrobial formulation, wherein the at least one antimicrobial agentincludes a silver-based antimicrobial agent, and wherein the at leastone water permeable polymer includes at least one of a polyurethane or athermoplastic polyurethane elastomer.
 19. The antimicrobial formulationof claim 18, wherein the at least one antimicrobial agent includes acombination of the silver-based antimicrobial agent and a polybiguanideor salt thereof.
 20. The antimicrobial formulation of claim 18, whereinthe at least one antimicrobial agent includes a combination of silversulfadiazine and chlorhexidine diacetate.